Statistics from Altmetric.com
IBD is characterised by an inappropriate immune response to our own gut microbiota in the setting of a genetically susceptible individual. The consequence of this dysregulated process is activation of the innate immune system which in turn produces cytokines such as tumour necrosis factor α (TNFα) and activation of the adaptive immune system with subsequent recruitment of pro-inflammatory T and B cells to the colon or small bowel. This in turn leads to further amplification of pro-inflammatory cytokines release which bind to cognate receptors and activation of intercellular pathway such as JAK and STAT to mediate tissue inflammation. The mainstay of treatment for individuals with moderate to severe disease UC or Crohn's disease has been therapeutic targeting of the pro-inflammatory cytokine, TNFα. Unfortunately, a significant proportion of individuals will be refractory to these medications or eventually lose efficacy. This has widened the search for other pathways that might be targeted to treat IBD. The most advanced of these treatments are the integrin inhibitors that target trafficking of lymphocytes to the gut.1
The maintenance of gut immunity is critically dependent on regional immune responses that are generated in the gut-associated lymphoid tissues. Dendritic cells (DCs) are positioned within the lamina propria in close relation to the enterocytes to continuously monitor the micro environment for potential antigens. Once an antigen is detected, gut DCs migrate to the mesenteric lymph nodes and the Peyer's patches. Within these secondary lymphoid tissues, DCs imprint on naive T and B cells’ knowledge of the antigen to generate an appropriate immune response. DC–lymphocyte priming conveys recognition of the antigen and the shape of the immune response required such as a pro-inflammatory response to a potentially harmful pathogen or tolerance to an auto-antigen. A third consequence of this interaction is the induction of the gut specificity on these newly programmed lymphocytes. This is an important feature of regional immunity so that immune cells are generated and directed back to the site where they are most likely to encounter the antigen, in this case the gut.2
Gut specificity is driven by gut-derived DCs that express CD1033 and have the unique ability to convert retinol to all-trans retinoic acid which in turn induces the expression of the chemokine receptor, CCR9 and the integrin combination, α4β7 on B and T lymphocytes during priming.4 ,5 This provides a molecular postal code to selectively recruit these lymphocytes to the gut where restricted expression of the chemokine, CCL25 (ligand for CCR9) and the α4β7 integrin ligand, MAdCAM-1 acts in tandem as molecular Velcro to capture gut-homing lymphocytes2 (figure 1). Other integrin ligands are also expressed in the gut during inflammation and do not add to tissue specificity but are generic to inflammation such as VCAM-1 (ligand for α4β1).
The first molecule to successfully target gut-specific adhesion and provide a paradigm for this strategy in treating IBD was natalizumab which targeted the α4 integrin.6 α4 Can associate with either β1 which binds to VCAM-1 or β7 which binds to MAdCAM-1. This drug proved efficacious in patients with moderate to severe Crohn's disease. Unfortunately, some individuals treated with natalizumab developed progressive multifocal leucoencephalopathy which is a rare, fatal demyelinating disease of the brain caused by reactivation of JC virus. Reactivation of JC virus is thought to be related to the α4β1 inhibitory effects of natalizumab.
Subsequently, much work has been done to selectively target α4β7 specifically without interfering of α4β1 to limit unwanted systemic immunosuppression. Several compounds have emerged as potential candidates. This includes etrolizumab (Genentech) which selectively targets β7 (phase II development) and PF-00547659 (Pfizer) as a selective inhibitor of MAdCAM-1, the ligand for α4β7 (phase I/II development). The most successful new drug in this class is vedolizumab which has been developed by Millennium Pharmaceuticals and Takeda. This molecule selectively targets the combination of α4β7 as a heterodimer with minimal effects individually on α4 or β7. Its potential utility in IBD came from studies in Cotton-top tamarins where rapid and dramatic improvements were seen at 24 and 72 h after treatment. This resulted in significant improvements in gut histology and reduction in mucosal T cell infiltration.7
Vedolizumab has subsequently shown clinical efficacy in randomised, placebo-controlled studies as an induction and maintenance therapy in moderate to severe UC (Gemini 1 study),8 moderate to severe Crohn's disease (Gemini 2)9 and moderate to severe Crohn's disease patients who had previously failed other treatments (Gemini 3).10 It was given FDA approval in May 2014 and ongoing safety data are being collected in the Gemini LTS study which is a 7-year study that aims to report in 2016. The majority of adverse events have been headache, nasopharyngitis, nausea, arthralgia, upper respiratory infections and fatigue. Serious infections tended to occur more frequently in Crohn's disease rather than UC.
The study by Wyant et al 11 published in this edition of Gut builds on the existing data of vedolizumab as a gut selective therapy by assessing the effects of vedolizumab on humoral responses following intestinal or systemic immunisation. The reasoning behind the study is to gain more evidence for its gut specificity and assess its impact on gut antibody-producing B cells. In the study, the investigators performed a phase I randomised, double blind, placebo-controlled study where 127 individuals were randomly assigned in a 1 : 1 ratio to receive either a single dose of vedolizumab 750 mg or placebo. This dose of vedolizumab is higher than the 300 mg that has been used in the clinical trials but was picked to ensure that serum drug concentrations led to complete α4β7 saturation of peripheral blood leucocytes for the subsequent 74 days. In addition to either receiving vedolizumab or placebo, individuals were also assigned an intramuscular dose of HBV vaccine on days 4, 32 and 60 of the study and an oral dose of the oral cholera vaccine (OCV) on days 4 and 18. Vaccine responses were assessed at day 74 and safety up to day 127. Immunity to HBV was defined as an anti-Hepatitis B surface antigen (HBS) antibody serum concentration of greater than 10 IU/L and for OCV it was defined as >4-fold increase from the baseline in the combined antibody titre (immunoglobulin (Ig)G, IgM and IgA). HBV seroconversion was similar between placebo treated (90.3%) and vedolizumab treated (88.7%) participants. However, the placebo treated group responded better to the OCV with 96.8% responses compared with 82.5% responses in the vedolizumab treated group. Anticholera immunoglobulin levels were higher in the placebo group than the vedolizumab group at day 74 (9210.08 vs 3007.8 units/mL).
The data support a selective role for vedolizumab in regional gut immunity and raise questions whether vedolizumab will be associated in the longer term with an excess of gut infections. This has not been brought out in the clinical trials and although in this study there is a reduction in the antibody responses, the majority of the cases were still able to generate sufficient protection from the OCV. It suggests that even at a relatively high dose, vedolizumab is not able to completely abrogate gut humeral responses. This is likely due to redundancy with α4β1 and is an important observation as IBD patients are more prone to gut infections and require appropriate immune responses to control enteric viruses and bacteria. The authors conclude that vedolizumab is able to modulate immune responses in the gut without compromising the host defences. Further clinical data will be required to confirm this observation and will hopefully be generated through the long-term Gemini LTS Safety Study.
Contributors BE compiled the data and wrote the manuscript.
Funding Canadian Institutes for Health Research (CIHR).
Competing interests None.
Provenance and peer review Commissioned; internally peer reviewed.
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.